Association of factor expression levels with annual bleeding rate in people with haemophilia B

Abstract

Introduction: Gene therapy clinical trials measure steady-state clotting factor expression levels (FELs) to evaluate the modulation of the bleeding phenotype, aiming to offer consistent protection against breakthrough bleeding events. The link between FELs and bleeding risk in people with haemophilia B (PwHB) is not well understood. Aim:We evaluated the association between FEL and ABR in PwHB. Methods:This cross-sectional study extended the CHESS burden of illness studies in Europe and the United States. Recruitment of additional adult males with haemophilia B supplemented the existing CHESS sample size of PwHB and FELs. PwHB receiving prophylaxis were excluded, as fluctuating FELs may have confounded the analysis.Demographic and clinical characteristics were reported descriptively. Any recorded baseline FEL was reported by the haemophilia-treating physicians according to the medical records. Generalised linear models with log link explored the association between changes in FEL and ABR. Results:The study included 407 PwHB and no inhibitors receiving on-demand treatment. Mean age was 36.7 years; 56% from the EU, 44% from the United States. Mean baseline FEL was 9.95 IU/dl (SD, 10.47); mean ABR was 2.4 bleeds/year (SD, 2.64). After adjusting for covariates, the model showed that for every 1% increase in FEL the average ABR decreased by .08 (p < .001). Predicted number of bleeding events according to FEL showed a significant non-linear relationship between FEL and ABR (p < .05). Conclusion:This analysis showed a significant relationship between FEL and ABR, where increases in FEL were associated with decreases in ABR among men with HB in Europe and the US.

The current challenges faced by people with hemophilia B

“…Real‐world outcomes of PWHB in Europe and the Unites States saw that, when receiving standard half‐life ( n = 114) or EHL ( n = 36) FIX replacement products, only 19% and 32% of PWHB, respectively, experienced no bleeds in the previous year, suggesting the occurrence of breakthrough bleeds in some PWHB 16 . Further to this, a recent study of PWHB in Europe and the Unites States ( N = 407) demonstrated that increases in FIX expression levels were significantly associated with decreases in annualized bleeding rate; for every 1% increase in FIX expression levels, the average annualized bleeding rate decreased by 0.08 ( p < .001) 17 . To achieve higher factor trough levels, PWHB may need to infuse factor replacement products more frequently or use higher doses.…”

“…16 Further to this, a recent study of PWHB in Europe and the Unites States (N = 407) demonstrated that increases in FIX expression levels were significantly associated with decreases in annualized bleeding rate; for every 1% increase in FIX expression levels, the average annualized bleeding rate decreased by 0.08 ( p < .001). 17 To achieve higher factor trough levels, PWHB may need to infuse factor replacement products more frequently or use higher doses. The recent international consensus recommendations for PWHB go beyond this, identifying how recommendations have been extrapolated from pharmacokinetic (PK) data on PWHA.…”

Recombinant factor IX Fc for the treatment of hemophilia B

“…5-10 IU/dL are associated with substantial reductions in bleed risk, while activity levels >25 IU/dL may be necessary to prevent all bleeding events for some products. 73 Fluctuating plasma activity levels during FIX prophylaxis are also a consideration when managing bleed risk. 72 For some patients, peak plasma activity levels and/or time above trough are more relevant than minimum trough levels.…”

“…However, even higher levels may be needed. Recent analyses indicate factor activity levels consistently in the range of 5–10 IU/dL are associated with substantial reductions in bleed risk, while activity levels >25 IU/dL may be necessary to prevent all bleeding events for some products 73 …”

Gene Therapy for Hemophilia B: Achievements, Open Issues, and Perspectives

“…1 4 With the use of clotting factor concentrates, some patients still experience breakthrough bleeds due to variable, often suboptimal, trough levels according to the lifestyle of the patients and schedule of treatment. 1 4 5 6 7 This of course increases the risk of the development of arthropathy, which negatively influences lifestyle and quality of life. 1 8 Recent developments have led to extended half-life products using techniques like PEGylation, Fc fusion, and albumin fusion, which improve stability and reduce infusion frequency.…”